Therapeutic compositions containing piperidine derivatives and methods of treating cough and pain therewith



United States Patent 3,456,060 THERAPEUTIC COMPOSITIONS CONTAININGPIPERIDINE DERIVATIVES AND METHODS OF TREATING COUGH AND PAIN THERE-WITH Hans Herbert Kuhnis, Hugo Ryf, and Rolf Denss, Basel, Switzerland,assignors to Geigy Chemical Corporation, Ardsley, N.Y., a corporation ofNew York No Drawing. Continuation-impart of application Ser. No.562,533, July 5, 1966. This application Aug. 16, 1967, Ser. No. 660,909Claims priority, applicatigi /S6v;itzerland, Jan. 15, 1965,

Int. Cl. A61k 27/00 US. Cl. 424-267 24 Claims ABSTRACT OF THE DISCLOSURETherapeutic compositions containing as active ingredients N-substituted4-allylor 4-(methylallyl)-4-acyloxypiperidines or their pharmaceuticallyacceptable acid addition salts, which compounds exhibit pronouncedactivity On the central nervous system, a first subclass of saidcompounds being particularly useful as antitussives with mild analgesicactivity, a second subclass as analgesics of medium strength, and athird subclass as strong analgesics, as well as processes for thepreparation of said compositions; methods of treating cough and/or painby administering these compounds or therapeutic compositions containingthem to mammals requiring such treatment. Illustrative embodiments ofthe active ingredients according to the invention are, e.g.,1-n-octyl-4allyl-4-propionoxypiperidine hydrochloride,l-methyl-4-allyl-4-acetoxypiperidine hydrochloride,l,4-diallyl-4-propionoxy-piperidine hydrochloride andl-(2'-phenylethyl)-4-allyl-4-acetoxy-piperidine hydrochloride.

CROSS REFERENCE TO RELATED APPLICATIONS This application is acontinuation-in-part of our copending patent application Ser. No.562,533, filed July 5, 1966, now US. Patent 3,338,910, issued Aug. 29,1967, which is a continuation-in-part of our copending patentapplication Ser. No. 520,093, filed Jan. 12, 1966, now US. Patent3,408,357 issued Oct. 29, 1968, the latter being in turn acontinuation-in-part of our copending patent application Ser. No.382,955, filed July 15, 1964, now US. Patent 3,366,638, issued Jan. 30,1968.

DETAILED DISCLOSURE This invention relates to methods for therapeutictreatment and to compositions useful for this purpose.

More particularly the invention pertains to methods for the treatment ofcough and/ or pain in mammals involving the administration to saidmammals of an effective amount of a piperidine derivative as hereinafterdefined, or a pharmaceutically acceptable acid addition salt thereof, orof a therapeutic composition containing these compounds in combinationwith a pharmaceutical carrier. It is also an object of the invention toprovide therapeutic compositions consisting essentially of (1) apiperidine derivative as hereinafter defined, or a pharmaceuticallyacceptable acid addition salt thereof, and (2) a pharmaceutical carner,

3,456,060 Patented July 15, 1969 In general the structure of thepiperidine derivatives which are employed in this invention may berepresented as follows:

In the above formula R may be exemplified for alkyl as, e.g, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. butyl, n-amyl,isoamyl, n-hexyl or n-octyl; for alkenyl as eg allyl, crotyl ormethallyl; for unsubstituted phenylalkyl as e.g, benzyl, phenylethyl orphenylpropyl; for phenylalkyl substituted in the phenyl moiety as e.g.halogenobenzyl, especially chlorobenzyl, fluorobenzyl and bromobenzyl,as lower alkoxy-benzyl, lower alkylbenzyl and 3,4-methylenedioxy-benzyl,as well as e.g. phenylethyl and phenyl-propyl bearing in the phenylmoiety the substituents named in the foregoing for benzyl,

The term lower used in this specification and the appended claims inconnection with an aliphatic group means that such group has up to 4carbon atoms inclusive.

A first preferred embodiment of piperidine derivatives particularlyvaluable for use in this invention are those compounds of the aboveformula wherein R represents alkyl of between 4 and 8 carbon atomsinclusive or benzyl,

each of R R R and R represents hydrogen, and R represents methyl orethyl.

Another, second, preferred embodiment of piperidine derivativesparticularly valuable for use in this invention are those compounds ofthe above formula wherein R represents alkyl of at most 3 carbon atoms,allyl,

phenylethyl or phenylpropyl, R respresents hydrogen or methyl,

each of R R and R represents hydrogen, and R represents (a) ethyl, whenR is phenylethyl, and R R R and R are as defined above, or

(b) methyl or ethyl, when R is alkyl of at most 3 carbon atoms, allyl orphenylpropyl, and R R R and R are as defined above.

Still another, third, preferred embodiment of piperidine derivativesparticularly valuable for use in this invention are those compounds ofthe above formula wherein R represents phenylethyl, each of R R and Rrepresents hydrogen, R represents hydrogen or methyl, and R represents(a) methyl, when R R R R and R are as defined above, or

(b) ethyl, when R R R and R are as defined above,

and R is methyl.

Also included within the scope of the present invention are thepharmaceutically acceptable addition salts of the above piperidinederivatives with inorganic or organic acids. By pharmaceuticallyacceptable addition salts of the bases usable according to the inventionare meant salts with those acids the anions of which arepharmacologically acceptable in the usual dosages, i.e. they have notoxic effects. It is also of advantage if the salts to be usedcrystallise well and are not or are only slightly hygroscopic. Examplesof pharmaceutically acceptable salts are the salts with hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonicacid, ethane sulfonic acid, fi-hydroxy-ethane sulfonic acid, aceticacid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleicacid, malic acid, tartaric acid, citric acid, benzoic acid, salicylicacid, phenylacetic acid, mandelic acid and embonic acid.

Piperidine derivatives according to the invention, i.e. those of FormulaI, as well as their addition salts with inorganic or organic acids,exhibit, on preferably oral and parenteral administration, valuablepharmacological properties, among which there are, in particular,central nervous depressant as well as antitussive and also analgesicactivity with, at the same time, a favorable therapeutic index, whilenot being liable to cause addiction, Their pharmacological properties,which are illustratively demonstrated further below, render thesepiperidines and their acid addition salts well suited for reducingtussive irritation and for the treatment of cough and also for thetreatment, relief and removal, of pain of various origin, in mammals,and thus for the use as active ingredients in therapeutic compositionsaccording to the invention.

Piperidine derivatives of the first preferred embodiment of theinvention are especially pronounced anti-tussives with mild analgesicactivity and are thus useful in the treatment of cough and tussiveirritation, particularly in the treatment of tussive conditions wheremild analgesic action is also desirable.

Piperidine derivatives of the second preferred embodiment of theinvention in particular exhibit analgesic action of medium strengthwhile being, at the same time, free from causing respiratory depression,whereas piperidine derivatives of the third preferred embodiment of theinvention are distinguished by especially strong analgesic activity. Byvirtue of these pharmacological properties the piperidines of the secondand the third preferred embodiment of the invention are particularlyuseful for the treatment, relief and removal, of pain of various origin;the compounds of the above third embodiment are thereby preferablyadministered parenterally.

The pharmacological action of the compounds of the invention mayillustratively be demonstrated, for example,

by means of the test described by R. Domenjoz, Archiv fiirexperimentelle Pathologie und Pharmakologie, 215, 19-24 (1952), the testdescribed by F. Gross, Helvet. Physiol. Acta, 5, C31 (1947) with theapparatus of H. Friebel, the test based on the procedure described by F.Hafi'ner, Deutsche Medizinische Wochenschrift, 24, 731 (1929), the testfollowing the method of A. D. Woolfe and G. McDonald, J. Pharmacol.Exptl. Therap., 80, 300 1944) and the screening method for testing theinfluence on respiration of rabbits with the use of the apparatusdescribed by Ch. Beaufort, Ann, Univ, araviensis, Med., VI/3 4, 6-2 2 4In the test described by R. Domenjoz healthy cats of normal weight arenarcotized with a suitable narcotic. Doses of 30-65 mg./kg. ofaprobarbital are applied intra- -peritoneally to obtain a relativelysuperficial narcosis.

About 45 minutes after the injection of the narcotic, the preparation ofthe nervus laryngeus superior is started, by fitting on anirritation-electrode. An apparatus manufactured by Grass MedicalInstruments, Type SDS, allowing irritation of the aforesaid nerve withrectangular current-impulses of any desired frequency and intensityis-connected to the electrode. The irritation-frequency applied is 5cycles at an irritation-intensity between 0.5 and 3 volts. Theirritation-duration is about 8 seconds and the interval between twoirritations is about seconds. For the registrations of the coughreflexes, a Marey capsule is used. A respiration-cannula is introducedthrough the oral cavity down to the glottic chink. The compound to betested is injected intravenously in the form of a 1% aqueous solution ofits hydrochloride.

Excellent antitussive activity is shown in this test forl-n-octyl-4-allyl-4propionoxy-piperidine hydrochloride in doses of about0.5 to 1.0 mg./k-g., and for 1-n-butyl-4- allyl-4-propionoxy-piperidinehydrochloride and l-benzyl- 4-allyl-4-acetoxy-piperidine hydrochloridein doses of about 1.0 to 2.0 mg./ kg.

The apparatus of Friebel used in the test described by F. Grosscomprises an electrically heated lamp which is placed in the focus of asemi-elliptical metal, concave mirror. Under the mirror, on aturn-table, there are located 10 small Plexiglas cages each holding awhite mouse in such a position that the mouse-tail rests stretched outin a small groove on a Plexiglas plate. The turn-table can be turned sothat the mouse-tails one after the other come to be placed into thesecond focus of the elliptical mirror. Pain is induced by the convergentheat radiation from the mirror and the time is measured from the momentwhen the heat reaches the mouse-tail till the moment at which the mousetwitches its tail.

Two series of 10 mice each are tested prior to the administration of thetest compound, and the normal reaction time for each mouse is recorded.Then the test compound is administered either by intraperitonealinjection or orally and the reaction times after the administration arerecorded, thus enabling determination of the intensity and the durationof the analgesic effect of the test compound administered.

l-n-octyl 4 allyl 4 propionoxy piperidine hydrochloride exhibits in thistest during 60 minutes an average increase of 50% of the threshold ofirritation (prolongation of reaction time) at doses of 48 mg./kg. p.o.,while having at the same time a favorable therapeutic index: thetoxicity value LD of this compound in the rat is 700 mg./kg. p.o.

Respective data shown in this test for other representative compoundsaccording to the invention are as follows:

Dose producing an average For 1-methyl-4-(1-methyla1lyl) 4 propionoxypiperidine hydrochloride, l-(2'-phenylethyl) -4-alkyl-4-propionoxy-piperidine hydrochloride and 1,4-diallyl-4-propionoxy-piperidine hydrochloride the above mentioned 50% increase ofthe threshold of irritation is observed at doses ranging from about 20.0to about 100.0

mg./kg. p.o. and about 10.0 to about 30.0 rug/kg. i.p., respectively,the LD for 1-methyl-4-(1'-methylallyl)-4- propionoxy-piperidinehydrochloride thereby being 30 mg./kg. i.v. mouse; the respective 50%increase of the threshold of irritation is further observed at doses offrom about 2.0 to about 10.0 mg./kg. i.p. for 1-(2- phenylethyl)-4-allyl4 acetoxy piperpidine hydrochloride, and 1(2'-phenylethyl)-3 methyl 4allyl 4- propionoxy-piperidine hydrochloride, respectively.

In the test based on the procedure described by F. Haifner for each doseof test substance 20 mice of both sexes (weight 20-25 g.) are examinedto see whether they react to a pressure stimulus. A control pressure of3 kg. is applied to the base of the mouse tail with forceps. A fullpain-reaction is shown by the squealing of the animals, their turningand biting the forceps. Animals which do not completely react to thispreliminary test, which seldom happens, are excluded from the test. Theanimals are then given the test preparations, either as an aqueoussolution i.p. or as a suspension with gum arabic p.o. The animals whichare treated i.p. are tested for pain caused by pressure at 15 minuteintervals during one hour. If, at the end of the first hour, still acertain effect is to be demonstrated, the number of animals which re-'act to the forceps pressure is also determined after 90 and 120 minutes.The animals treated per os are not submitted to the first test, since itcan be assumed that insuflicient test substance has been absorbed atthat time.

The animals which react to the applied pressure by turning, squealingand/or biting are considered as having a full reaction to pain, thosewhich only turn are deemed /2 sensitive. Mice which do not react at allare considered completely analgetic, and those with incomplete painreaction (only turning movement) /2 analgetic. The results of theanalgesia-test are expressed by the maximal number of analgetic(not-reacting) animals during the observation period. If not at least20% insensitive animals can be ascertained, the preparation can beconsidered as practically ineffective against this strong pain stimulus.

With doses of 100 mg./kg. p.o. of 1-(2'-phenylethyl)-4-allyl-4-acetoxy-piperidine hydrochoride 40% of insensitive animals areascertained, and with 75 mg./kg. i.p. of1-'(2'-phenylethyl)-3-methyl-4-allyl 4 propionoxypiperidinehydrochloride 50% of the animals remain insensitive.

In the test following the method of A. D. Woolfe et al. pain is producedin groups each of 20 albino mice (weigh ing from 14 to 18 grams) byplacing the animals in a vessel having a bottom plate heated to 56 C.The reaction time, i.e. the time from the beginning of the exposure ofeach animal till the observation of a pain reaction, namely licking orshaking of its front paw or jumping, is determined. This reaction timeis measured twice pror to the application of the test compound. The testcompound is then administered either per us through a stomach tube ori.p. to each test animal and the reaction time is again determined, andat 30, 45, 60, and 120 minutes after such application. The prolongationof reaction time after administration of the test compound is indicatedin percent of the reaction time obtained prior to administration. Theintensity of analgesic activity is represented by the mean value of thedata obtained during the first hour of the application of the testcompound.

1-(Z'-pheny1ethyl)-4-allyl 4 acetoxy piperidine hydrochloride showed ata dose of 50 mg./kg. p.o. a prolongation of the reaction time of about32%, and 1-(2'- phenyletheyl)-3-methyl-4-allyl 4 propionoxy -piperidinehydrochloride prolonged the reaction time about 101% at a dose of 50mg./kg. i.p., the first compound thereby exhibiting an LD of 240mg./-kg. p.o. in the rat, the second compound an LD of 590 mg./kg. p.o.in the mouse.

In the screening method for testing the influence on respiration ofrabbits with the use of the apparatus described by Ch. Beaufort,respiration frequency and respiration volume are registered. In thistest, e.g. l-methyl- 4-allyl 4 acetoxy piperidine hydrochlorideexhibited in doses up to 10 mg/kg. i.v. no action on the respirationvolume and frequency.

It is well known that N-su-bstituted 4-hydroxy-4-phenylethynyl and4-acyloxy-4-propynyl-piperidines show pronounced pharmacologicalactivity of a general central nervous depressant type and are reportedto have an analgesic activity which is not of the morphine-type; andthat a few of them apear also to be useful as antitussives. Thisactivity on the central nervous system appears to be adscri'bable to theelectronic configuration of a CEC bond in the respective substituents in4-position at the piperidine nucleus, for it is also known thatreduction, e. g., of the phenylethynyl to the cisand trans-styrylanalogs results in loss of the central nervous effects.

It is, therefore, not to be expected that in the case of the compoundsaccording to this aspect of the invention which are allyl analogs of theabove mentioned 4-propynyl-substituted piperidines, no such loss, but onthe contrary, very pronounced activity on the central nervous system isfound.

For their intended uses the piperidine derivatives according to theinvention may be administered, preferably, orally or, in the form ofaqueous solutions of appropriate pharmaceutically acceptable acidaddition salts thereof, also parenterally, but may also be administerede.g. rectally, in amounts depending on the species, age and weight ofthe subject under treatment as well as on the particular condition to betreated and, of course, the mode of administration; in general, thedaily dosages of the piperidine derivatives of the invention, or theirpharmaceutically acceptable acid addition salts, vary between about 1.0mg. and about 800 mg; more particularly, in the case of stronganalgesics according to the invention, about 1.0 mg. to not more than50.0 mg. are indicated as daily dosage, and in the case of antitussivesand medium strength analgesics according to the invention about 100 mg.to about 800 mg. as daily dosage are preferred.

For administration purposes preferably therapeutic compositions are usedconsisting essentially of a piperidine derivative according to theinvention, or a pharmaceutically acceptable addition salt thereof withan inorganic or organic acid, in combination with a pharmaceuticalcarrier and, if desired, further additives. These compositions arepresented for oral or parenteral administration in solid and liquiddosage units, respectively, such as tab lets, dragees (sugar coatedtablets), capsules, ampoules, and the like; for rectal administrationthey are presented in form of suppositories, rectal capsules, etc.; eachdosage unit preferably contains between about 1.0 mg. to about 200.0 mg.of an inventive piperidine derivative or a pharmaceutically acceptableacid addition salt thereof, as active ingredient.

In suitable dosage units for oral administration such as dragees (sugarcoated tablets), tablets or capsules, the amount of active ingredient ispreferably 1% to To produce tablets or dragee cores, the activesubstance is combined with, e.g. solid pulverulent carriers such aslactose, saccharose, sorbitol or mannitol; starches such as potatostarch, maize starch or amylopectin, also laminaria powder or citruspulp powder; cellulose derivatives or gelatine, optionally with theaddition of lubricants such as magnesium or calcium stearate orpolyethylene glycols of suitable molecular weights, to form tablets ordragee cores. The latter are coated, e.-g. with concentrated sugarsolutions which can also contain, e.g. gum arabic, talcum and/ortitanium dioxide, or with a lacquer dissolved in easily volatile organicsolvents or mixtures of solvents. Dyestuifs can be added to thesecoatings, e.g. to distinguish between diflerent dosages of activesubstance. Other suitable oral dosage units are hard gelatine capsulesas well as soft, closed capsules made from gelatine and a softener suchas glycerol. The former contain the active substance and the carrier,preferably as a granulate, in admixture with lubricants such as talcumor magnesium stearate and, optionally, appropriate stabilisers. In softcapsules, the active substance is preferably dissolved or suspended insuitable liquid carriers such as liquid polyethylene glycols;stabilisers can also be added.

In addition, for the treatment of coughs in particular, also, forexample, lozenges as well as liquid forms for oral administration notmade up into single dosages such as cough syrups prepared with the usualauxiliaries, and drops can be considered.

Dosage units for rectal administration are, e.g. suppositories whichconsist of a combination of a piperidine derivative of Formula I or asuitable salt thereof using as carrier a neutral fatty foundation, oralso gelatine rectal capsules which contain a combination of the activesubstance or a suitable salt thereof with polyethylene glycols(Carbowaxes) of suitable molecular weight as carriers.

Ampoules for parenteral, particularly intramuscular, administrationpreferably contain as active ingredient a water soluble pharmaceuticallyacceptable acid addition salt of an inventive compound, the carrierbeing water. The concentration of the active ingredient is preferablybetween 0.5% and If necessary, suitable stabilising agents and/or buffersubstances are added to the ampoule solutions.

The following prescriptions further illustrate the production oftablets, dragees, syrups, drops and ampoules:

(a) 250 g. of 1-methyl-4-allyl-4-acetoxy-piperidine hydrochloride aremixed with 175.80 g. of lactose and 169.70 g. of potato starch, themixture is moistened with an alcoholic solution of g. of stearic acidand granulated through a sieve. After drying, 160 g. of potato starch,200 g. of talcum, 2.50 g. of magnesium stearate and 32 g. of colloidalsilicon dioxide are mixed in and the mixture is pressed into 10,000tablets each weighing 100 mg. and containing 25 mg. of active substance.The tablets can be grooved if desired for better adaptation of thedosage.

(b) A granulate is produced from 250 g. of l-methyl-4-allyl-4-acetoxy-piperidine succinate, 175.90 g. of lactose and thealcoholic solution of 10 g. of stearic acid. After drying, the granulateis mixed with 56.60 g. of colloidal silicon dioxide, 165 g. of talcum,20 g. of potato starch and 2.50 g. of magnesium stearate and the Wholeis pressed into 10,000 dragee cores. These are then coated with aconcentrated syrup made of 522.28 g. of crystalline saccharose, 6 g. ofshellack, 10 g. of gum arabic, 215 g. of talcum, g. of colloidal silicondioxide, 0.22 g. of dyestuff and 1.5 g. of titanium dioxide and dried.The dragees obtained each weigh 145 mg. and contain 25 mg. of activesubstance.

(c) To produce a cough syrup, g. of 1-n-octyl-4-allyl-4-propionoxy-piperidine hydrochloride, 42 g. of phydroxy-benzoicacid methyl ester, 18 g. of p-hydroxybenzoic acid propyl ester and 5,000g. of crystallised sugar and also any flavouring desired are dissolvedin distilled water up to 10 litres.

(d) T o produce drops for the treatment of coughs, 500 g. of1-n-butyl-4-allyl-4-propionoxy-piperidine hydrochloride, 10 g. ofascorbic acid, sweetener, e.g. 5 g. of sodium cyclamate, flavouring asdesired and 2,500 g. of sorbitol (70%) are dissolved in distilled waterup to 10 litres.

(e) 10 g. of active substance, e.g. 1-(2-phenylethyl)- 3 methyl4-allyl-4-propionoxy-piperidine hydrochloride are dissolved in distilledwater up to a volume of 1 litre. This solution is used to fill ampoules,each of 1 ml., containing 10 mg of active substance.

The compounds of the invention may be prepared-by known methods as, forexample, described in our copending patent application Ser. No. 562,533,filed July 5, 1966.

Representative piperidine derivatives and acid addition salts thereofwhich may be employed in the instant invention are particularly thosewhich are described and listed 8. in thefollowing non-limitativeexamples; these examples are also illustrative for. the preparation ofsaid compounds. Percentages in the preceding specification and in theseexamples are given by weight. The temperatures are given in degreescentigrade; torr means mm. Hg.

.Example 1 10.2 g. of magnesium filings in 30 ml. of abs. ether areplaced in a 750 ml. four-necked flask and a little allyl bromide isadded dropwise while stirring. As soon as the reaction has begun, ml. ofabs. ether are added and 50.8 g. of allyl bromide are added dropwise insuch a way that the ether remains boiling under reflux and then thewhole is stirred for another 10 minutes. 28.2 g. of1-propyl-4-piperidone in 50 ml. of abs. ether are then added dropwise,the whole is refluxed for 15 minutes, heating is interrupted and 109.2g. of propionic acid anhydride in 70 ml. of abs. benzene are addeddropwise. The yellowish suspension is then refluxed for 6 hours, pouredonto ice, made acid with concentrated hydrochloric acid and the etherealphase is extracted three times with 6 N hydrochloric acid. The combinedacid extracts are made alkaline withv concentrated ammonia, extractedfour times with chloroform, dried, concentrated and distilled. The1-propyl-4-a1lyl-4-pr6- pionoxy-piperidine boils at 88 /0.04 torr. Thehydrochloride is produced therefrom with ethereal hydrochloric acid inabs. ether. It melts at 225-226 (recrystallised from isopropanol/ether).

The following compounds are' produced in the same way:

1-propyl-4-allyl-4-acetoxy-piperidine, B.P. 75 0.03 torr,

hydrochloride M.P. 227; 1-methyl-4-allyl-4-propionoxy-piperidine, B.P.70-75/ 0.06 torr, hydrochloride M.P. 157-158";1-methyl-4-allyl-4-acetoxy-piperidine, B.P. 5965/ 0.05

torr, hydrochloride M.P. 167-168;1-(2'-phenylethyl)-4-allyl-4-acetoxy-piperidine, B.P. 136- 140/0.02torr, hydrochloride M.P. 246;1-(2-pheny1ethyl)-4-allyl-4-propionoxy-piperidine, B.P.

152/ 0.05 torr, hydrochloride M.P. 228-230; 1-(3-phenylpropyl)-4-allyl-4-acetoxy-piperidine, B.P. 149154 0.05 torr,hydrochloride M.P. 1821831-(3'-phenylpropyl)-4-allyl-4-propionoxy-piperidine, B.P.

155-160/0.01 torr, hydochloride M.P. 148149;1-ethyl-4-allyl-4-propionoxy-piperidine, B.P. 70-72/ 0.01

torr, hydrochloride M.P. 176-177", citrate M.P. 173- 174;1-ethyl-4-allyl-4-acetoxy-piperidine, B.P. 70 0.01 torr,

hydrochloride M.P. 183; citrate M.P. 158;1,4-diallyl-4-acetoxy-piperidine, B.P. 65-66/ 0.015 torr,

hydrochloride M.P. 173174; 1,4-diallyl-4-propionoxy-piperidine, B.P.8790/ 0.05 torr,

hydrochloride M.P. 205-207"; 1-benzyl-4-allyl-4-acetoxy-piperidine,hydrochloride, M.P.

197-198"; 1-n-butyl-4-a1lyl-4-acetoxy-piperidine, hydrochloride,

M.P. 238; 1-n-butyl-4-allyl-4-propionoxy-piperidine, hydrochloride,

M.P. 222; 1-cyclohexyl-4-'ally1-4-acetoxy-piperidine, hydrochloride,

M.P. 250; 1-cyclohexy1-4-allyl-4-propionoxy-piperidine, hydrochloride,M.P. 234; 1-n-octyl-4-allyl-4-acetoxy-piperidine, hydrochloride,

M.P. 221222; 1-n-octyl-4-allyl-4-propionoxy-piperidine, hydrochloride,

M.P. 196-197"; 1-isopropyl-4-allyl-4-acetoxy-piperidine, hydrochloride,

M.P. 220; 1 1-isopropyl-4-allyl-4-propionoxy-piperidine, hydrochloride,M.P. 198199; 1-(2-phenyl-ethyl)-3-methyl-4-allyl-4-acetoxy-piperidine,maleate, M.P. 130-131; l

1- (2'-phenyl-ethyl) -3-rnethyl-4-ally1-4-propionoxypiperidine, maleate,M.P. 117-118 and 1-methyl-4-(2'-butenyl) -4-acetoxy-piperidine, citrate,

l-(p-methoxybenzyl)-4-al1yl-4-acetoxy-piperidine, hydrochloride;

1-(p-rnethoxybenzyl)-4-allyl-4-propionoxy-piperidine,

hydrochloride;

1- 3 ,4-dimethoxybenzyl -4-allyl4-acetoxy-piperidine,

hydrochloride;

1- 3,4-dimethoxybenzyl) -4-allyl-4-propionoxy-piperidine,

hydrochloride;

1-(3,4,5-trimethoxybenzyl)-4-allyl-4-acetoxy-piperidine,

hydrochloride;

1-( 3,4,5 -trimethoxybenzyl -4-allyl-4-p ropionoxy-piperidine,hydrochloride;

l-(p-methylbenzyl)-4-allyl-4-acetoxy-piperidine, hydrochloride;

1- p-methylbenzyl) -4-allyl-4-propionoxy-piperidine,

hydrochloride;

1-( m-methylbenzyl)-4-allyl-4-acetoxy-piperidine, hydrochloride;

1- rn-methylbenzyl -4-allyl-4-propionoxy-piperidine,

hydrochloride;

1-( o-methylbenzyl)-4-allyl-4-acet0xy-piperidine, hydrochloride;

1-(o-methylbenzyl)-4-allyl-4-propionoxy-piperidine,

hydrochloride;

1-(2,3-dimethylbenzyl)-4-allyl-4-acetoxy-piperidine,

hydrochloride;

l- (2,3 -dimethylbenzyl) -4-allyl-4propionoxy-piperidine,

hydrochloride;

1-(3,4-dimethylbenzyl)-4-allyl-4-acetoxy-piperidine,

hydrochloride;

1- 3,4-dimethylbenzyl)-4-allyl-4-propionoxy-piperidine,

hydrochloride;

1-(2,6-dimethylbenzyl)-4-allyl-4-acetoxy-piperidine,

hydrochloride;

1-(2,6-dimethylbenzyl)-4-allyl-4-propionoxy-piperidine,

hydrochloride;

1- 2,4,6-trimethylb enzyl) -4allyl-4-acetoxy-piperidine,

hydrochloride;

1-(2,4,6-trimethylbenzyl) -4-a1lyl-4-propionoxy-piperidine,

hydrochloride;

1-( 3 ,4-methylenedioxybenzyl) -4-allyl-4-acetoxy-piperidine,hydrochloride;

1- 3 ,4-rnethylenedioxyb enzyl) -4-allyl-4-propionoxypiperidine,hydrochloride;

l-(p-chlorobenzyl)-4-allyl-4-acetoxy-piperidine, hydrochloride;

1-(p-chlorobenzyl)-4-allylA-propionoxy-piperidine,

hydrochloride;

l-(2,4-dichlorobenzyl)-4-allyl-4-acetoxy-piperidine, hy-

drochloride;

l- 2,4-dichlorobenzyl) -4-allyl-4-propionoxy-piperidine,

hydrochloride;

l- 2,6-dichlorobenzyl -4-allyl-4-acetoxy-piperidine, hy-

drochloride;

1-(2,6-dichlorobenzyl)-4-allyl-4-propionoxy-piperidine,

hydrochloride;

l- (p-fluorobenzyl) -4-allyl-4-acetoxy-piperidine, hydrochloride;

l-(p-fluorobenzyl)-4-allyl-4-propionoxy-piperidine, hy-

drochloride;

1-(2,6-dichloro-3-methylbenzyl)-4-allyl-4-acetoxy-piperidine,hydrochloride;

1-(2,6-dich1oro-3-methylbenzyl)-4-a1lyl-4-propionoxypiperidine,hydrochloride;

l-(p-bromobenzyl)-4-allyl-4-acetoxy-piperidine, hydrochloride;

1-(p-bromobenzyl)-4-a1lyl-4-propionoxy-piperidine, hy-

drochloride;

l-(p-methoxyphenethyl)-4-allyl-4-acetoxy-piperidine, hy-

drochloride;

1 (p-meth oxyphenethyl) -4-allyl-4-propionoxy-pip eridine,

hydrochloride;

1 (3 ,4-dimetl1oxyphenethyl) -4-allyl-4-propionoxy-piperidine,hydrochloride;

1- 3,4,5-trimethoxyphenethyl) -4allyl-4-propionoxy-piperidine,hydrochloride;

l-(p-methylphenethyl)-4-a1lyl-4-acetoxy-piperidine, hy-

drochloride;

lp-methylphenethyl) -4-allyl-4-propionoxy-piperidine,

hydrochloride;

1- (o-methylphenethyl) -4-allyl-4-propionoxy-piperidine,

hydrochloride;

1- (3 ,4-methylenedioxyphenethyl) -4-allyl-4-propionoxypiperidine,hydrochloride;

I-(p-chlorophenethyl) -4-allyl-4-acetoxy-piperidine, hy-

drochloride;

l (p-chlorophenethyl -4-allyl-4-propionoxy-piperidine,

hydrochloride;

1 (2,4-dichloroph enethyl) -4-allyl-4-propionoxy-piperidine,hydrochloride;

1 p-fluorophenethyl -4-allyl-4-p ropionoxy-pip eridine,

hydrochloride;

1- (p-bromophenethyl -4-allyl-4-propionoxy-piperidine,

hydrochloride;

1- [3- p-methoxyphenyl) -propyl] -4-allyl-4-acetoxy-piperidine,hydrochloride;

1- 3- (-p-methoxyphenyl) -propyl] -4-allyl-4-propionoxypiperidine,hydrochloride;

1- 3- 3,4-dimethoxyphenyl) -propyl] -4-allyl-4-propionoxy-piperidine,hydrochloride;

1- [3- 3,4,5 -trimethoxyphenyl -propyl]-4-allyl-4-propionoxy-piperidine, hydrochloride;

1- [3- (p-tolyl) -propyl] -4-allyl-4-acetoxy-piperidine, hy-

drochloride;

1- 3- (p-tolyl -propyl] -4-allyl-4-pr0pionoxy-piperidine,

hydro chloride;

1 3 (o-tolyl -propyl] -4-allyl-4-propionoxy-pipe ridine,

hydrochloride;

1- [3- (3 ,4-methylenedioxy-phenyl -propyl] -4-allyl-4-propionoxy-piperidine, hydrochloride;

1- 3- (p-chlorophenyl -propyl] -4-allyl-4-acetoxy-piperidine,hydrochloride;

1 [3 p-chlorophenyl -propyl] -4-allyl-4-propionoxy-piperidine,hydrochloride;

1- [3- 3,4-dichlorophenyl) -propyl] -4-al1yl-4-propion0xypiperidine,hydrochloride;

1- 3 p-fluorophenyl -propyl] -4-allyl-4-propionoxy-piperidine,hydrochloride;

1- [3 -(p-bromopl1enyl) -propyl] -4-allyl-4-propionoxy-piperidine,hydrochloride.

Example 2 14.58 g. of magnesium filings in 25 ml. of abs. ether areplaced in a 1500 ml. four-necked flask and a little crotyl bromide(l-bromo-Z-butene) is added dropwise. When the reaction has started, 215ml. of abs. ether are added and the remainder of 27 g. of crotyl bromideis slowly added over 4-5 hours while stirring. The reaction mixture isthen stirred for another 30 minutes, 11.3 g. of l-methyll -piperidone inml. of abs. ether are added in 10 minutes, the mixture is refluxed for30 minutes, 50 ml. of acetanhydride are added and the yellow suspensionis refluxed for another tWo hours. The mixture is then poured onto ice,acidified With concentrated hydrochloric acid, and the ethereal phase isextracted three times with 6 N hydrochloric acid. The combined acidextracts are made alkaline with concentrated ammonia, extracted fourtimes With chloroform, the chloroform solution is dried and concentratedand the residue is distilled. The1-methyl-4-(1'-methylallyl)-4-acetoxy-piperidine boils at 59-65 0.05torr.

The hydrochloride is produced by adding ethereal hydrochloric acid tothe solution of the base in abs. ether. It melts at 198 (recrystallisedfrom acetone).

1-methyl-4-( 1-methylallyl) -4-propionoxy-piperidine is produced in thesame way. Its hydrochloride melts at 207 (recrystallised fromacetone/isopropanol).

Example 3 (a) 5.1 g. of magnesium filings in 15 ml. of ether are placedin a 350 ml. flask and a little allyl bromide is added dropwise. Whenthe reaction has started, 60 ml. of abs. ether are added and theremainder of 25.4 g. of allyl bromide are so added while stirring thatthe ether remains boiling under reflux. The whole is then stirred foranother 10 minutes whereupon 11.3 g. of 1-methyl-4-piperidone in 30 ml.of abs. ether are slowly added, After refluxing for 30 minutes, ice isadded to the mixture which is then acidified with concentratedhydrochloric acid and the ethereal phase is extracted three times with 6N hydrochloric acid. The combined acid extracts are made alkaline withconcentrated ammonia and extracted with chloroform, the chloroformsolution is dried and concentrated and the residue is distilled. The1-methyl-4-allyl- 4-piperidinol boils at 6064/0.01 torr; the citratemelts at 9597 (recrystallised from methanol/ ether). l-propyl-4-allyl-4-piperidinol, B.P. 69-76/0.02 torr, is obtained in the sameway.

(b) 7.6 g. of the product of (a) are refluxed for 3 hours with 40 ml. ofacetanhydride. The reaction solution is then evaporated in a rotaryevaporator, ice is added to the residue which is then made stronglyalkaline and extracted five times with chloroform. The chloroformsolution is dried and concentrated and the residue is distilled. The1-methyl-4-allyl-4-acetoxy-piperidine boils at 112- 115/12 torr; thehydrochloride melts at 167-168 (recrystallised from isopropanol/ether).

1-methyl-4-allyl-4-propionoxy-piperidine is produced in the same way.The hydrochloride melts at 157l58 (recrystallised fromisopropanol/ether),

Example 4 3.5 g. of 1-methyl-4-allyl-4-piperidinol hydrochloride and 250mg. of p-toulene sulphonic acid are dissolved in 150 ml. of chloroform.Ketene freshly prepared from acetone is passed through this solution(Quedbeck apparatus, Angew. Chemie 68, 369 (1956)). The progress of thereaction is followed by thin layer chromatography (silica gel with 0.5%sodium hydroxide solution, eluant: methanol). No more starting materialcan be determined after 15 minutes. The solution turns yellow during thereaction and the temperature rises about 40. The solution isconcentrated to half its volume and extracted twice with 100 ml. of 2 Nhydrochloric acid each time. The acid solution is made alkaline withsodium carbonate, the product which precipitates is extracted threetimes with 100 ml. of ether each time, dried with anhydrous sodiumsulphate and concentrated. The oily 1-methyl-4-allyl-4-acetoxypiperidineis converted into the citrate. M.P. of citrate 181".

Example 5 2 g. of 1-methyl-4-(2'-propinyl)-4-acetoxy-piperidine arehydrogenated at room temperature under normal pressure with 500 mg. ofpalladium-cacO -lead acetate catalyst and 200 mg. of quinoline, Afterthe calculated amount of hydrogen has been taken up (about 23 minutes),the catalyst is filtered off, the filtrate is evaporated and the residueis distilled. The hydrochloride of 1-methyl-4-allyl-4-acetoxy-piperidine produced from the distillate melts at 167-168" andis identical with the product produced analogously to Example 1.

Example 6 5.64 g. of magnesium in 15 ml. of abs. ether are placed in aGrignard apparatus and 31.3 g. of methallyl bromide are added by firstentering 2-3 ml. thereof, and, as soon as the reaction has started, 60ml. of ether and then the remainder of the methallyl bromide, the latterbeing added dropwise within 30 minutes. The whole is then refluxed 10minutes and the N-methyl piperidone is added to 40 ml. of ether. Afterthe reaction has subsided, the solution is refluxed for 30 minutes. 50ml. of propionic acid anhydride in 50 ml. of abs. benzene are then addedand the whole is refluxed for 6 hours. Ice and concentrated hydrochloricacid are then added, the acid phase is removed and the organic phase isextracted twice with 2 N hydrochloric acid. The aqueous extracts arecombined, made alkaline with concentrated ammonia, extracted four timeswith chloroform, dried, evaporated and distilled. The 1-methyl-4-methallyl-4-propionoxy-piperidine boils under 0.04 torr at60-65. The citrate is produced therefrom in the usual way and isrecrystallised from methanol when it then melts at 177-178.

Example 7 5 g. of 1-methyl-4-allyl-4-acetoxy-piperidine hydrochlorideare dissolved in 30 ml. of water, the solution is rendered alkaline byadding concentrated sodium hydroxide solution, and is then extractedfour times with chloroform. The combined extracts are dried overanhydrous sodium sulfate, and evaporated to dryness in a rotaryevaporator; the residue is dissolved in 25 ml. of anhydrous diethylether, and methane sulfonic acid is added until the methane sulfonatesalt has been precipitated quantitatively. The latter is separated byfiltration and is recrystallized three times from acetone, M.P. -1405".

In a similar manner there are produced from the correspondinghydrochlorides and the desired acid, the following pharmaceuticallyacceptable salts of compounds produced according to Examples 1 t0 6:

1-n1ethyl-4-allyl-4-acetoxy-piperidine citrate, M.P.

1-methyl-4-allyl-4-acetoxy-piperidine succinate, M.P.

l-methyl-4-allyl-4-acetoxy-piperidine maleate.

The succinates, methanesulfonates, citrates and maleates of each of thefree bases listed below are obtained by reaction of their hydrochloridesand the corresponding acids in accordance with Example 7, supra.

1-methyl-4-( 1'-methylallyl) -4-acetoxy-piperidine,1-methyl-4-allyl-4-propionoxy-piperidine,

1- (2-phenylethyl) -4-allyl-4-propionoxy-piperidine, 1benzyl-4-allyl-4-acetoxy-piperidine,1-'(n-butyl)-4-allyl-4-propionoxy-piperidine,

1- (n-o ctyl -4-allyl-4-propionoxy-pip eridine,1-(2'-phenylethyl)-4-allyl-4-acetoxy-piperidine.

From 1 (2' phenylethyl) 3 methyl 4 allyl 4- propionoxy-piperidinemaleate, the hydrochloride, succinate, methanesulfonate and citrate areobtained according to Example 7, by reaction with hydrochloric acid,succinic acid, methane sulfonic acid and citric acid, respectively.

Analogously, 1 (2' phenylethyl) 3 methyl 4- allyl-4-acetoxy-piperidinemaleate is converted into the hydrochloride, succinate, methanesulfonateand citrate.

What is claimed is:

1. A therapeutic composition for the treatment of pain and coughconsisting essentially of an effective amount of (1) a compound of theformula s Ra-CH==41 Ila-Cg /0-C0-Ri 0 mo \CHR4 H: CH:

wherein R represents alkyl of at most 8 carbon atoms,

alkenyl of from 3 to 8 carbon atoms, cyclohexyl, unsubstitutedphenylalkyl of at most 9 carbon atoms, or phenylalkyl of at most 9carbon atoms substituted in the phenyl moiety by chloro, bromo, fiuoro,lower alkoxy, lower alkyl or 3,4-methylenedioxy, each of R R R, and Rrepresents hydrogen or methyl,

and R represents methyl or ethyl, or a pharmaceutically acceptable acidaddition salt thereof, and

(2) a pharmaceutical carrier.

2. A therapeutic composition for the treatment of pain and coughconsisting essentially of an effective amount of 1) a compound of theformula wherein R represents alkyl of between 4 and 8 carbon atomsinclusive or benzyl, each of R R R and R represents hydrogen, and Rrepresents methyl or ethyl, or a pharmaceutically acceptable acidaddition salt thereof, and

(2) a pharmaceutical carrier.

3.A therapeutic composition as defined in claim 2 wherein in saidcompound R represents n-octyl, each of R R R and R represents hydrogen,and R represents ethyl.

4. A therapeutic composition as defined in claim 2 wherein in saidcompound R represents n-butyl, each of R R R and R represents hydrogen,and R represents ethyl.

5. A therapeutic composition as defined in claim 2 wherein in saidcompound R represents benzyl, each of R R R and R represents hydrogen,and R represents methyl.

6. A therapeutic composition for the treatment of pain and coughconsisting essentially of an efiective amount of (1) a compound of theformula wherein R represents alkyl of at most 3 carbon atoms,

allyl, phenylethyl or phenylpropyl, R represents hydrogen or methyl,each of R R and R represents hydrogen, and R represents (a) ethyl, whenR is phenylethyl, and R R R and R are as defined above, or

14 (b) methyl or ethyl,

when R is alkyl of at most 3 carbon atoms, allyl or phenylpropyl, and RR R and R are as defined above, or a pharmaceutically acceptable acidaddition salt thereof, and

(2) a pharmaceutical carrier.

7. A therapeutic composition as defined in claim 6 in in said compound Rrepresents methyl, each of R R R R and R represents hydrogen, and Rrepresents methyl.

8. A therapeutic composition as defined in claim 7 wherein thepharmaceutically acceptable acid addition salt of said compound is thesuccinate or the hydrochloride.

9. A therapeutic composition as defined in clainii 6 wherein in saidcompound R represents methyl, R represents methyl, each of R R and Rrepresents hydrogen, and R represents ethyl.

10. A therapeutic composition as defined in claim 6 where in saidcompound R represents allyl, each of R R R and R represents hydrogen,and R represents ethyl.

11. A therapeutic composition as defined in claim 6 wherein in saidcompound R represents phenylethyl, each of R R R and R representshydrogen, and R represents ethyl.

12. A therapeutic composition for the treatment of pain and coughconsisting essentially of an etfective amount of (1) a compound of theformula wherein R represents phenylethyl, each or R R and R representshydrogen, R represents hydrogen or methyl, and R reprsents (a) methyl,when R R R R and R are as defined above, or (b) ethyl, when R R R and Rare as defined above, and R is methyl, or a pharmaceutically acceptableacid addition salt thereof, and

(2) a pharmaceutical carrier.

13. A therapeutic composition as defined in claim 12 wherein in saidcompound R represents phenylethyl, each of R R R and R representshydrogen, and R represents methyl.

14. A therapeutic composition as defined in claim 12 wherein in saidcompound R represents phenylethyl, each of R R and R representshydrogen, R represents methyl and R represents ethyl.

15. A method of treating pain which comprises administering to a mammalrequiring such treatment an analgesically effective amount of a compoundof the formula wherein R represents alkyl of at most 8 carbon atoms,

alkenyl of from 3 to 8 carbon atoms, cyclohexyl,

unsubstituted phenylalkyl of at most 9 carbon atoms,

or phenylalkyl of at most 9 carbon atoms substituted in the phenylmoiety by chloro, bromo, fluoro, lower alkoxy, lower alkyl or3,4-methylenedioxy,

each of R R R and R represents hydrogen or methyl, and R representsmethyl or ethyl,

or a pharmaceutically acceptable acid addition salt thereof.

16. A method of treating pain which comprises administering to a mammalrequiring such treatment an analgesically effective amount of a compoundofthe for-' mula R5 R30H=o (DH-R4 wherein 1 R represents alkyl of atmost 3 carbon atoms, allyl,

17. A method as defined in claim 16- wherein in said compound Rrepresents methyl, each of R R R and R represents hydrogen, and Rrepresents methyl.

1 8. A method as defined in claim 17 wherein the pharmaceuticallyacceptable acid addition salt of said compoundisihe succinate or thehydrochloride.

" .19. A method as defined in claim 16 wherein in saidcompound Rrepresents methyl, R represents methyl, each of R R and R representshydrogen, and R represents ethyl.

20. A method. as defined: in claim 16 wherein in' said compound R'representsallyl, each-of R R R and R represents hydrogen, *and' Rrepresents ethyl. 1

2-1. A method as defined in claim 16 wherein in said compound Rrepresents phenylethyl, each oil-R R R and R represents hydrogen, andRrepresents ethyl.

22. A method of treatingpain which comprises administering to a mammalrequiring such treatment an analgesically effective amount of a compoundof the for- R represents phenylethyl, I

1 each of R R and R represents hydrogen, R represents hydrogenonmethyL-and't' R represents (a) methyl, when R ,R R R; and R are as vcompound R represents phenylethyl, each of R R and R representshydrogen, R represents methyl, and R represents ethyl. 1

References .Cited UNITED STATES PATENTS 2,798,073 7/1957 Lee etal260284;3 3,081,309 '3/1963 Prost\ 260-2843 ALBERT T. MEYERS, PrimaryExaminer S. I. FRIEDMAN, Assistant Examiner

